Preoperative Exercise during Neoadjuvant Therapy for Pancreatic Cancer: A Pilot Study

Exercise improves cancer treatment outcomes including health-related quality of life and physical functioning. Patients with pancreatic cancer are generally older adults, and frailty and cachexia are prevalent. Chemotherapy and chemoradiation are increasingly administered prior to pancreatic cancer surgery, and sarcopenia has been shown to accompany these therapies. Preoperative exercise may improve health, well-being, and perioperative outcomes among patients undergoing preoperative therapy for pancreatic cancer. The purpose of this pilot study was to determine the feasibility of exercise in this context. Feasibility was defined as patients completing, on average, 60% of recommended weekly exercise minutes. Twenty patients (M=64 years old, SD=9.9; 42% female) enrolled in a home-based exercise program during preoperative therapy (chemotherapy and/or chemoradiation and preoperative “rest”, M=21.2 weeks total, SD=16.4). Exercise recommendations included moderate-intensity walking for 20-30 minutes/day on ≥3 days/week and moderate-intensity resistance exercises for 30-45 minutes/day on ≥2 days/week. Exercise recommendations (120 minutes of moderate-intensity activity/week) were based on American College of Sports Medicine and American Cancer Society recommendations (150 minutes of moderate-intensity activity/week), but reduced due to patients’ older age and concurrent preoperative therapy. Resistance exercises targeted upper body, lower body, and abdominal muscles, and patients were instructed to perform 3 sets of 8-12 repetitions of multiple exercises for each region during each session. Patients received Yamax Digiwalker pedometers, graded resistance tube sets, and booklets and DVDs with instructions and safety tips. Research staff provided detailed instructions and resistance exercise demonstrations at enrollment and monitored and encouraged adherence with biweekly phone calls. Patients recorded minutes of walking and resistance exercise in daily logs. On average, patients reported 73.9 minutes of walking (\u3e100% of recommendation, SD=72.4) and 43.1 minutes of resistance exercise per week (71.8% of recommendation, SD=39.0). Patients reported the most walking during chemoradiation (M=94.7 minutes/week, SD=104.3), followed by preoperative “rest” (M=77.4 minutes/week, SD=80.4), and chemotherapy (M=70.8 minutes/week, SD=75.2). Patients reported the most resistance exercise during the preoperative “rest” period (M=51.6 minutes/week, SD=52.3), followed by chemoradiation (M=38.0 minutes/week, SD=36.8), and chemotherapy (M=31.1 minutes/week, SD=38.1). Walking and resistance exercise are feasible for patients undergoing preoperative therapy for pancreatic cancer. Varying levels of fatigue and treatment-related side effects may affect exercise during different treatment phases

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Identification of rare microbial colonizers of plastic materials incubated in a coral reef environment

Plastic waste accumulation in marine environments has complex, unintended impacts on ecology that cross levels of community organization. To measure succession in polyolefin-colonizing marine bacterial communities, an in situ time-series experiment was conducted in the oligotrophic coastal waters of the Bermuda Platform. Our goals were to identify polyolefin colonizing taxa and isolate bacterial cultures for future studies of the biochemistry of microbe-plastic interactions. HDPE, LDPE, PP, and glass coupons were incubated in surface seawater for 11 weeks and sampled at two-week intervals. 16S rDNA sequencing and ATR-FTIR/HIM were used to assess biofilm community structure and chemical changes in polymer surfaces. The dominant colonizing taxa were previously reported cosmopolitan colonizers of surfaces in marine environments, which were highly similar among the different plastic types. However, significant differences in rare community composition were observed between plastic types, potentially indicating specific interactions based on surface chemistry. Unexpectedly, a major transition in community composition occurred in all material treatments between days 42 and 56 (p < 0.01). Before the transition, Alteromonadaceae, Marinomonadaceae, Saccharospirillaceae, Vibrionaceae, Thalassospiraceae, and Flavobacteriaceae were the dominant colonizers. Following the transition, the relative abundance of these taxa declined, while Hyphomonadaceae, Rhodobacteraceae and Saprospiraceae increased. Over the course of the incubation, 8,641 colonizing taxa were observed, of which 25 were significantly enriched on specific polyolefins. Seven enriched taxa from families known to include hydrocarbon degraders (Hyphomonadaceae, Parvularculaceae and Rhodobacteraceae) and one n-alkane degrader (Ketobacter sp.). The ASVs that exhibited associations with specific polyolefins are targets of ongoing investigations aimed at retrieving plastic-degrading microbes in culture

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years

Priority setting for the implementation of artemisinin-based combination therapy policy in Tanzania: evaluation against the accountability for reasonableness framework

\ud Priority setting for artemisinin-based antimalarial drugs has become an integral part of malaria treatment policy change in malaria-endemic countries. Although these drugs are more efficacious, they are also more costly than the failing drugs. When Tanzania changed its National Malaria Treatment Policy in 2006, priority setting was an inevitable challenge. Artemether-lumefantrine was prioritised as the first-line drug for the management of uncomplicated malaria to be available at a subsidized price at public and faith-based healthcare facilities. This paper describes the priority-setting process, which involved the selection of a new first-line antimalarial drug in the implementation of artemisinin-based combination therapy policy. These descriptions were further evaluated against the four conditions of the accountability for easonableness framework. According to this framework, fair decisions must satisfy a set of publicity, relevance, appeals, and revision and enforcement conditions.In-depth interviews were held with key informants using pretested interview guides, supplemented with a review of the treatment guideline. Purposeful sampling was used in order to explore the perceptions of people with different backgrounds and perspectives. The analysis followed an editing organising style. Publicity: The selection decision of artemether-lumefantrine but not the rationale behind it was publicised through radio, television, and newspaper channels in the national language, Swahili. Relevance: The decision was grounded on evidences of clinical efficacy, safety, affordability, and formulation profile. Stakeholders were not adequately involved. There was neither an appeals mechanism to challenge the decision nor enforcement mechanisms to guarantee fairness of the decision outcomes. The priority-setting decision to use artemether-lumefantrine as the first-line antimalarial drug failed to satisfy the four conditions of the accountability for reasonableness framework. In our understanding, this is the first study to evaluate priority-setting decisions for new drugs in Tanzania against the accountability for reasonableness framework. In addition to the demand for enhanced stakeholder involvement, publicity, and transparency, the study also calls for the institution of formal appeals, revision, and regulatory mechanisms in the future change of malaria treatment policies.\u

Parkinsons disease variant detection and disclosure: PD GENEration, a North American study.

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinsons disease; however, individuals with Parkinsons disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinsons disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinsons disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinsons disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more high risk factors for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinsons disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinsons disease

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Highlights of the ERS Lung Science Conference and Sleep and Breathing Conference 2021 and the new ECMC members

The Lung Science Conference (LSC) and the Sleep and Breathing Conference (SBC) are two conferences organised by the European Respiratory Society (ERS), the latter held in association with the European Sleep Research Society. This year, the LSC and SBC were both held in a virtual format with the participation of researchers and clinicians from around the world. The participation of Early Career Members (ECMs) was notable in both events: 216 of 363 (60%) delegates attending the LSC were under 40?years old, and 315 of 920 (34%) delegates were ?40?years of age at the SBC. Both conferences included outstanding talks on the most recent advances in respiratory medicine and science, oral/poster communication sessions on novel research, exciting opportunities to network with peers, and much more!This paper provides a brief overview of some of the most remarkable sessions of the LSC and SBC, written by ECMs attending the sessions.We also present the new members of the Early Career Member Committee (ECMC) of the ERS from Assemblies 1, 4, 10, 12 and 13, who were elected in the latest round of ERS elections. Welcome aboard